Gene Therapy for Huntington’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 126

rotarod, clasping, and open field behavioral tests. Furthermore,
the number of intranuclear inclusions, BrdU-positive cells, and
striatal volume was not significantly different from control animals.
This lack of efficacy may be attributable to the late delivery of
GDNF since disease onset occurs early in R6/2 mice [ 48 ] and
irreversible disease processes may have already been activated.
These results show that timing of treatment can be crucial for the
attainment of therapeutic response and it may be pertinent to tar-
get HD at its early stages.

Neurturin (NRTN) is another member of the GDNF family, shar-
ing approximately 40 % homology with GDNF, and possesses simi-
lar functional characteristics [ 41 , 49 ]. In the striatum, it binds to
the abundantly expressed GFRʱ-1 to activate c-Ret, promoting the
survival of projection neurons in the indirect pathway which inhibit
movement [ 50 ]. Given that HD is a hyperkinetic disorder, the
delivery of NRTN to the striatum may assist in alleviating motor
symptoms. Long-term striatal NRTN expression can be achieved by
AAV vectors for up to at least 1 year in a rat model of Parkinson's
disease [ 51 ]. Bilateral intrastriatal injections of AAV-NRTN prior to
3-NP intoxication in rats resulted in 24 % striatal cell loss as opposed
to 43 % in controls, indicating partial neuroprotection. In addition,
AAV-NRTN-treated rats exhibited gradual recovery in motor func-
tions, and their performance in the rotarod, raised platform tests,
and ambulatory behavior assessment were comparable to unle-
sioned animals [ 52 ]. In a subsequent study involving presymptom-
atic N171-82Q transgenic mice, AAV-NRTN delayed the onset
and attenuated the severity of rotarod deficits and clasping behav-
ior, as well as partially prevented stride length decline. AAV-NRTN
not only provided complete neuroprotection in the striatum but
also partially protected layers V and VI of the frontal and prefrontal
cortex where cortical cell loss is most prominent in HD [ 53 ].
In summary, a variety of growth factors have been shown to
protect striatal neurons to varying degrees, but they do not target
the pathogenic cause of HD. We next review some strategies aimed
at directly modulating pathogenic mHtt levels.

1.1.5 Neurturin

Increasing mHtt clearance may be an effective way to alleviate neu-
rodegeneration and subsequent symptoms by mitigating patho-
genic processes induced by the mutation. Intrabodies are
recombinant antibodies designed to inhibit or modulate protein
function in the intracellular environment [ 54 ]. Viral vector-based
gene delivery methods can facilitate the expression of antibody
fragments directed to specific intracellular protein targets, forming
the basis of intrabody therapy. Due to their versatility, the
therapeutic potential of intrabodies has been investigated in HD as
well as other neurodegenerative diseases presenting with misfolded
protein aggregates including Alzheimer's disease [ 55 , 56 ] and

1.2 Intrabodies